CN114053241A - Solid dispersion and controlled-release tablet containing policosanol and preparation method thereof - Google Patents
Solid dispersion and controlled-release tablet containing policosanol and preparation method thereof Download PDFInfo
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- CN114053241A CN114053241A CN202010783032.9A CN202010783032A CN114053241A CN 114053241 A CN114053241 A CN 114053241A CN 202010783032 A CN202010783032 A CN 202010783032A CN 114053241 A CN114053241 A CN 114053241A
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- Prior art keywords
- policosanol
- layer
- surfactant
- medicine
- controlled
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- 229960001109 policosanol Drugs 0.000 title claims abstract description 141
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 title claims abstract description 141
- 238000013270 controlled release Methods 0.000 title claims abstract description 62
- 238000002360 preparation method Methods 0.000 title claims abstract description 37
- 239000007962 solid dispersion Substances 0.000 title claims abstract description 33
- 239000003814 drug Substances 0.000 claims abstract description 92
- 239000004094 surface-active agent Substances 0.000 claims abstract description 47
- 239000002245 particle Substances 0.000 claims abstract description 43
- 239000000945 filler Substances 0.000 claims abstract description 30
- 239000000314 lubricant Substances 0.000 claims abstract description 26
- 239000000853 adhesive Substances 0.000 claims abstract description 24
- 230000001070 adhesive effect Effects 0.000 claims abstract description 24
- 239000006185 dispersion Substances 0.000 claims abstract description 17
- 239000002736 nonionic surfactant Substances 0.000 claims abstract description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 75
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 57
- -1 polyoxyethylene Polymers 0.000 claims description 50
- 239000008187 granular material Substances 0.000 claims description 42
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 34
- 239000011248 coating agent Substances 0.000 claims description 32
- 238000000576 coating method Methods 0.000 claims description 32
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 30
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 29
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 29
- 239000000463 material Substances 0.000 claims description 28
- 238000002156 mixing Methods 0.000 claims description 28
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 25
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 24
- 229940079593 drug Drugs 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 21
- 239000002202 Polyethylene glycol Substances 0.000 claims description 20
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 20
- 229920001223 polyethylene glycol Polymers 0.000 claims description 20
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 16
- 239000011780 sodium chloride Substances 0.000 claims description 15
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 14
- 239000000194 fatty acid Substances 0.000 claims description 14
- 229930195729 fatty acid Natural products 0.000 claims description 14
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 13
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 13
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 12
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 11
- 239000011230 binding agent Substances 0.000 claims description 11
- 239000008101 lactose Substances 0.000 claims description 11
- 239000012876 carrier material Substances 0.000 claims description 10
- 235000019359 magnesium stearate Nutrition 0.000 claims description 10
- 150000003904 phospholipids Chemical class 0.000 claims description 10
- 150000003445 sucroses Chemical class 0.000 claims description 8
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 7
- 239000007888 film coating Substances 0.000 claims description 7
- 238000009501 film coating Methods 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- 235000021355 Stearic acid Nutrition 0.000 claims description 6
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 6
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 6
- 229920000136 polysorbate Polymers 0.000 claims description 6
- 229940068965 polysorbates Drugs 0.000 claims description 6
- OKODKVMXHLUQSW-JITBQSAISA-M sodium;(e)-4-hydroxy-4-oxobut-2-enoate;octadecanoic acid Chemical compound [Na+].OC(=O)\C=C\C([O-])=O.CCCCCCCCCCCCCCCCCC(O)=O OKODKVMXHLUQSW-JITBQSAISA-M 0.000 claims description 6
- 239000008117 stearic acid Substances 0.000 claims description 6
- 238000005550 wet granulation Methods 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 5
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 5
- 238000004080 punching Methods 0.000 claims description 5
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 4
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 4
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 4
- 229930195725 Mannitol Natural products 0.000 claims description 4
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 4
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 4
- 150000002576 ketones Chemical class 0.000 claims description 4
- 239000000594 mannitol Substances 0.000 claims description 4
- 235000010355 mannitol Nutrition 0.000 claims description 4
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 4
- 239000000600 sorbitol Substances 0.000 claims description 4
- 235000010356 sorbitol Nutrition 0.000 claims description 4
- 239000000811 xylitol Substances 0.000 claims description 4
- 235000010447 xylitol Nutrition 0.000 claims description 4
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 4
- 229960002675 xylitol Drugs 0.000 claims description 4
- 229960003943 hypromellose Drugs 0.000 claims description 3
- 239000011148 porous material Substances 0.000 claims 1
- 239000003826 tablet Substances 0.000 description 120
- 239000010410 layer Substances 0.000 description 117
- 239000000243 solution Substances 0.000 description 59
- 238000003756 stirring Methods 0.000 description 38
- 238000005303 weighing Methods 0.000 description 24
- 238000005469 granulation Methods 0.000 description 15
- 230000003179 granulation Effects 0.000 description 15
- 238000001035 drying Methods 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- 238000010438 heat treatment Methods 0.000 description 9
- 229930006000 Sucrose Natural products 0.000 description 8
- 238000011049 filling Methods 0.000 description 8
- 239000005720 sucrose Substances 0.000 description 8
- 238000005516 engineering process Methods 0.000 description 6
- CNNRPFQICPFDPO-UHFFFAOYSA-N octacosan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCCCCO CNNRPFQICPFDPO-UHFFFAOYSA-N 0.000 description 6
- 239000003960 organic solvent Substances 0.000 description 6
- 229920002301 cellulose acetate Polymers 0.000 description 5
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 4
- 239000008199 coating composition Substances 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000011259 mixed solution Substances 0.000 description 4
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 4
- 229940093429 polyethylene glycol 6000 Drugs 0.000 description 4
- 238000007873 sieving Methods 0.000 description 4
- 229960002666 1-octacosanol Drugs 0.000 description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 3
- 239000011361 granulated particle Substances 0.000 description 3
- 150000002632 lipids Chemical class 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 3
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 2
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 2
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 2
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 2
- 208000032928 Dyslipidaemia Diseases 0.000 description 2
- 208000017170 Lipid metabolism disease Diseases 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 239000005642 Oleic acid Substances 0.000 description 2
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 2
- 235000021314 Palmitic acid Nutrition 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 150000005690 diesters Chemical class 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 238000001647 drug administration Methods 0.000 description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 150000002191 fatty alcohols Chemical class 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 150000002327 glycerophospholipids Chemical class 0.000 description 2
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 2
- 229940049964 oleate Drugs 0.000 description 2
- 235000021313 oleic acid Nutrition 0.000 description 2
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 2
- 229940057838 polyethylene glycol 4000 Drugs 0.000 description 2
- 238000006116 polymerization reaction Methods 0.000 description 2
- 229920000056 polyoxyethylene ether Polymers 0.000 description 2
- 229940069328 povidone Drugs 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000008347 soybean phospholipid Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 150000005691 triesters Chemical class 0.000 description 2
- 206010007269 Carcinogenicity Diseases 0.000 description 1
- 239000003390 Chinese drug Substances 0.000 description 1
- 108010028554 LDL Cholesterol Proteins 0.000 description 1
- 108010007622 LDL Lipoproteins Proteins 0.000 description 1
- 102000007330 LDL Lipoproteins Human genes 0.000 description 1
- 206010074268 Reproductive toxicity Diseases 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000007670 carcinogenicity Effects 0.000 description 1
- 231100000260 carcinogenicity Toxicity 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 239000007766 cera flava Substances 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 239000011247 coating layer Substances 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000004088 foaming agent Substances 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 239000001341 hydroxy propyl starch Substances 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 235000013828 hydroxypropyl starch Nutrition 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 231100001084 no genetic toxicology Toxicity 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 229940096978 oral tablet Drugs 0.000 description 1
- 230000001151 other effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000011112 process operation Methods 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000007696 reproductive toxicity Effects 0.000 description 1
- 231100000372 reproductive toxicity Toxicity 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to the technical field of policosanol preparations, and provides a solid dispersion containing policosanol, which comprises the policosanol, a surfactant and a carrier, wherein the surfactant is a nonionic surfactant for assisting dispersion; the particle size of the solid dispersion is not more than 5 μm. The invention provides a policosanol-containing controlled release tablet and a preparation method thereof, wherein the tablet comprises a double-layer tablet core and a controlled release film layer wrapping the double-layer tablet core; the double-layer tablet core consists of a medicine-containing layer and a boosting layer; the medicine-containing layer comprises policosanol, a surfactant, a filler, a carrier, an adhesive and a lubricant; the content of policosanol in each controlled release tablet is not less than 5 mg. The invention can greatly reduce the particle size of the policosanol in the medicament, improve the dispersion degree and the solubility of the policosanol, control the release rate of the policosanol, prolong the release time and the administration interval, and further improve the bioavailability and the administration compliance of the policosanol in a human body.
Description
Technical Field
The invention relates to the technical field of policosanol preparations, in particular to a policosanol-containing solid dispersion, a controlled-release tablet and a preparation method thereof.
Background
Policosanol is a mixture of eight higher fatty alcohols extracted from sucrose wax, such as octacosanol. Animal experiments show that policosanol can reduce the serum cholesterol and low-density lipoprotein (LDL-C) levels of normal and endogenous high-cholesterol animals. Various animal model researches show that policosanol can reduce cholesterol in liver, adipose tissue and heart. The active ingredient has little acute toxicity when orally administered, and has no genetic toxicity, reproductive toxicity and carcinogenicity.
Policosanol tablets were first developed by cubadarma laboratories ltd and were marketed in cuba in 1991 with approval from the cub drug administration. In China, the approval of the Chinese drug administration was obtained in 2006 for the earliest time and the drug was imported into China. The traditional policosanol tablet is a common tablet, and the prescription contains the effective component of policosanol and auxiliary materials such as a diluent (also called a filler) used by the conventional oral tablet. The initial dosage of the medicine for regulating dyslipidemia is 5mg daily, and is taken at dinner. If the effect is not significant, the dose can be increased to 10 mg/day (once in the noon and evening) and for refractory patients the dose can be increased to 20 mg/day, twice daily.
At present, the existing tablets are generally required to be taken twice a day, and the compliance of taking medicines by patients is low.
Disclosure of Invention
In view of the above, the present application provides a policosanol-containing solid dispersion, a controlled release tablet and a preparation method thereof, the solubility of the policosanol-containing solid dispersion in an oral preparation can be improved, and the controlled release tablet can slowly release the policosanol at a relatively constant speed, so that the pharmaceutical tablet can be taken once a day, the administration frequency is reduced, and the compliance is improved.
The invention provides a policosanol-containing solid dispersion, which comprises policosanol, a surfactant and a carrier, wherein the surfactant is a nonionic surfactant for assisting dispersion; the particle size of the policosanol in the solid dispersion is not more than 5 mu m, and the preferable range is not more than 1 mu m.
Preferably, the surfactant is selected from one or more of sucrose esters, phospholipids, polysorbates, and polyoxyethylene fatty acid esters; the carrier is selected from one or more of polyethylene glycol and polyvinylpyrrolidone.
In the policosanol-containing solid dispersion provided by the invention, the dispersion state of the policosanol is improved through the auxiliary dispersion of the nonionic surfactant and other effects; the policosanol in the solid dispersion has smaller particle size, the particle size is not more than 5 mu m, the preferable range is not more than 1 mu m, the solubility of the policosanol can be effectively increased, the oral bioavailability is improved, and the control of the release rate of the controlled release preparation in the release process is facilitated.
The invention provides a controlled release tablet containing policosanol, which comprises the following components: a double-layer tablet core and a controlled release film layer wrapping the double-layer tablet core; the double-layer tablet core consists of a medicine-containing layer and a boosting layer;
the medicine-containing layer comprises policosanol, a surfactant, a filler, a carrier, an adhesive and a lubricant; the surfactant is a nonionic surfactant for assisting dispersion; the content of policosanol in each controlled release tablet is above 5mg, preferably 5mg-80mg, more preferably 10mg-60 mg.
Preferably, the surfactant is selected from one or more of sucrose esters, phospholipids, polysorbates, and polyoxyethylene fatty acid esters; the content of the surfactant is 0.5-10 times of the mass of the policosanol, the preferable range is 0.5-5 times, and the more preferable range is 0.5-3 times.
Preferably, the filler is a water-soluble filler, preferably one or more of sodium chloride, lactose, polyoxyethylene, mannitol, sorbitol and xylitol, more preferably a combination of at least two of polyoxyethylene, sodium chloride and lactose.
Preferably, the carrier is selected from one or more of polyethylene glycol and polyvinylpyrrolidone; the content of the carrier is 1-20 times, preferably 2-10 times of the mass of the policosanol.
Preferably, the lubricant is selected from one or more of stearic acid, magnesium stearate and sodium stearyl fumarate, preferably sodium stearyl fumarate; the adhesive is selected from one or more of polyvinylpyrrolidone, hypromellose and hydroxypropyl cellulose.
Preferably, the controlled release film layer is mainly formed by a film coating material and a pore-forming agent and is provided with a plurality of drug release holes.
The invention also provides a preparation method of the controlled release tablet containing the policosanol, which comprises the following steps:
mixing policosanol, a surfactant, a carrier material and a solvent to obtain a medicine-containing solution; the drug-containing solution, the filler and the lubricant are granulated by a wet method to obtain drug-containing layer granules; optionally adding a binder to the drug-containing solution or during wet granulation;
respectively providing boosting layer particles and coating material solution;
tabletting the medicine-containing layer particles and the boosting layer particles to obtain a double-layer tablet core;
and coating the double-layer tablet core by adopting the coating material solution, and then punching to obtain the controlled-release tablet containing policosanol.
Preferably, heating the medicine-containing solution containing the policosanol, the surfactant and the carrier material to volatilize the solvent, so as to obtain a solid dispersion with the particle size of the policosanol not more than 5 microns; the solid dispersion, the adhesive, the filler and the lubricant are subjected to wet granulation to obtain the drug-containing layer granules.
Preferably, the solvent is selected from one or more of small molecule alcohol and ketone, preferably one or more of ethanol, propylene glycol, isopropanol and acetone; the mixing temperature is from 40 ℃ to 100 ℃, preferably in the range of from 50 ℃ to 90 ℃.
Compared with the common policosanol tablet, the invention provides a policosanol controlled-release tablet which has a double-layer tablet core structure and is coated with a controlled-release film coat; the main body of the preparation consists of a tablet core medicine-containing layer and a tablet core boosting layer, wherein the medicine-containing layer consists of a certain amount of policosanol, a surfactant, a filling agent, a carrier, an adhesive and a lubricant. In the invention, the content of policosanol in each controlled release tablet is more than 5mg, preferably 5mg-80 mg; the surfactant is a nonionic surfactant for assisting dispersion. The invention can greatly reduce the particle size of the policosanol in the medicament, improve the dispersion degree and the solubility of the policosanol, control the release rate of the policosanol, prolong the release time and the medicament taking interval, can take the medicinal tablets once a day, reduce the administration frequency and further improve the bioavailability of the policosanol in a human body and the compliance of medicament taking.
Detailed Description
The technical solutions in the embodiments of the present invention are clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The invention provides a policosanol-containing solid dispersion, which comprises policosanol, a surfactant and a carrier, wherein the surfactant is a nonionic surfactant for assisting dispersion; the particle size of policosanol in the solid dispersion is not more than 5 mu m.
The solid dispersion containing the policosanol provided by the invention has smaller particle size, can improve the dispersion degree and the solubility in an oral preparation, and further improves the bioavailability.
The solid dispersion is a preparation intermediate, and is a dispersion system formed by highly dispersing a drug in a solid carrier, and generally consists of the drug and the carrier.
The embodiment of the invention adopts a formula containing policosanol, a surfactant and a carrier, and can prepare the solid dispersion with smaller particle size of the policosanol. Wherein policosanol is effective component of medicine for regulating blood lipid abnormality, and is mixture containing eight kinds of higher fatty alcohols such as octacosanol extracted from Cera flava.
In the invention, the surfactant is a pharmaceutically acceptable nonionic (type) surfactant, and mainly plays a role in assisting dispersion. The nonionic surfactant is preferably one or more selected from sucrose esters, phospholipids, polysorbates and polyoxyethylene fatty acid esters, and more preferably sucrose esters, phospholipids or polyoxyethylene fatty acid esters. The sucrose ester is called sucrose fatty acid ester (SE) completely, and the HLB value distribution is wide; the current commercial products are mainly monoesters, diesters, triesters and mixed esters of sucrose esterified with stearic acid, palmitic acid or oleic acid. Phospholipids are a class of lipids containing phosphate groups, such as phosphoglycerides. The polyoxyethylene fatty acid ester, also called fatty acid polyoxyethylene (ether) ester, has hydrophilicity proportional to the degree of polymerization of ethoxy groups. The dosage of the surfactant is 0.5-10 times of the mass of the policosanol, the preferable range is 0.5-5 times, and the more preferable range is 0.5-3 times, so that the performance of the solid dispersion is facilitated.
In the embodiment of the present invention, a water-soluble carrier material is mainly used, and the carrier can be selected from one or more of polyethylene glycol (PEG) and polyvinylpyrrolidone (PVP, povidone). Wherein, the relative molecular mass of the polyethylene glycol can be 1000 to 30000, preferably 1000 to 20000, such as polyethylene glycol 2000, polyethylene glycol 4000, polyethylene glycol 6000, etc.; the relative molecular mass of the polyvinylpyrrolidone can be 2500-50000. The dosage of the carrier is 1-20 times, preferably 2-10 times of the mass of the policosanol.
The surfactant and the carrier in the formula amount are weighed in the embodiment of the invention, can be respectively added into the solvent in a certain proportion under the stirring state, are uniformly dispersed, and are preferably slowly heated to the set temperature to obtain the carrier solution. Wherein, the solvent can be selected from one or more of small molecular alcohol and ketone, preferably one or more of ethanol, propylene glycol, isopropanol and acetone, and more preferably ethanol and/or acetone.
Then, the policosanol in the prescribed amount is weighed in the embodiment of the invention, added into the carrier solution under stirring, and continuously stirred until the policosanol is dissolved, so as to obtain a drug-containing solution. The policosanol can be dissolved in hot organic solvents, such as ethanol, propylene glycol, isopropanol and acetone, preferably ethanol and acetone; the temperature of mixing or dissolving is 40 ℃ to 100 ℃, preferably in the range of 50 ℃ to 90 ℃.
In the embodiment of the invention, the medicine-containing solution containing policosanol, the surfactant and the carrier material is continuously heated to raise the temperature, wherein the temperature rise range is 40-100 ℃, and the preferred range is 50-90 ℃; dissolving policosanol in hot organic solvent, uniformly dispersing in mixture of other surfactant and carrier, volatilizing organic solvent to obtain solid dispersion containing policosanol with small particle size, pulverizing at low temperature, and sieving with 100 mesh sieve. The solid dispersion is typically a light yellow solid; wherein the particle size of the policosanol is not more than 5 μm, the preferable range is not more than 1 μm, such as 0.01-1 μm, the solubility of the policosanol can be effectively increased, and the control of the release rate of the controlled release tablet in the release process is facilitated.
In addition, the present invention provides a controlled-release tablet containing policosanol, comprising: a double-layer tablet core and a controlled release film layer wrapping the double-layer tablet core; the double-layer tablet core consists of a medicine-containing layer and a boosting layer;
the medicine-containing layer comprises policosanol, a surfactant, a filler, a carrier, an adhesive and a lubricant; the surfactant is a nonionic surfactant for assisting dispersion; the content of policosanol in each controlled release tablet is above 5 mg.
The policosanol-containing controlled-release tablet provided by the invention can slowly release policosanol at a relatively constant speed, so that the pharmaceutical tablet can be taken once a day, the taking frequency is reduced, and the compliance of taking medicine is improved.
The controlled release tablet provided by the embodiment of the invention is a double-layer controlled release tablet, wherein a double-layer tablet core consists of a tablet core drug-containing layer and a tablet core boosting layer and is coated with a controlled release film coat. In the double-layer tablet core, the medicine-containing layer consists of a certain amount of policosanol, a surfactant, a filling agent, a carrier, an adhesive and a lubricant. In the present invention, the policosanol content in each controlled-release tablet is 5mg or more, preferably 5mg to 80mg, more preferably 10mg to 60mg, for example, 10mg, 20mg, 30mg, 40mg, etc.
In the tablet core medicament-containing layer, the surfactant is a pharmaceutically acceptable nonionic (type) surfactant and is mainly used for assisting in dispersion. The nonionic surfactant is preferably one or more selected from sucrose esters, phospholipids, polysorbates and polyoxyethylene fatty acid esters, and more preferably sucrose esters, phospholipids or polyoxyethylene fatty acid esters. The sucrose ester is called sucrose fatty acid ester (SE) completely, and the HLB value distribution is wide; the current commercial products are mainly monoesters, diesters, triesters and mixed esters of sucrose esterified with stearic acid, palmitic acid or oleic acid. Phospholipids are a class of lipids containing phosphate groups, such as phosphoglycerides. The polyoxyethylene fatty acid ester, also called fatty acid polyoxyethylene (ether) ester, has hydrophilicity proportional to the degree of polymerization of ethoxy groups. The content of the surfactant is 0.5-10 times of the mass of the policosanol, the preferable range is 0.5-5 times, and the more preferable range is 0.5-3 times.
In the embodiment of the present invention, the filler is preferably a water-soluble filler, more preferably one or more of sodium chloride, lactose, polyoxyethylene, mannitol, sorbitol, and xylitol, and more preferably a combination of at least two of polyoxyethylene, sodium chloride, and lactose. The filler is matched with a surfactant and the like, and can control the release of the polycosanol at a relatively constant rate after contacting with water in a machine body. In some embodiments, the filler is a combination of polyoxyethylene and sodium chloride; in other embodiments, the filler is a combination of polyoxyethylene and lactose, and has good compatibility with drugs. The content of the filler is preferably 2 to 6 times, for example, 2, 3, 4, 5, 6 times, etc., the mass of the policosanol.
In the embodiment of the invention, a water-soluble carrier material is mainly adopted, and the carrier can be selected from one or more of polyethylene glycol (PEG) and polyvinylpyrrolidone (PVP and povidone). Wherein, the relative molecular mass of the polyethylene glycol can be 1000 to 30000, preferably 1000 to 20000, such as polyethylene glycol 2000, polyethylene glycol 4000, polyethylene glycol 6000, etc.; the relative molecular mass of the polyvinylpyrrolidone can be 2500-50000. The content of the carrier is 1-20 times, preferably 2-10 times of the mass of the policosanol.
The prescription of the medicine-containing layer of the tablet core also comprises a binding agent and a lubricant which are pharmaceutic adjuvants, wherein the lubricant can be one or more of stearic acid, magnesium stearate and sodium stearate fumarate, and is preferably magnesium stearate or sodium stearate fumarate, so that the surface characteristics of the prepared granules can be improved, and tabletting is convenient. In addition, the content of the lubricant can be 0.1-0.5 time of the mass of the policosanol, and the performance of the tablet is easily influenced by the excessive use amount. The binder may be polyvinylpyrrolidone, cellulose derivatives, etc., preferably one or more of polyvinylpyrrolidone, Hypromellose (HPMC) and hydroxypropyl cellulose (HPC), more preferably polyvinylpyrrolidone.
The controlled release tablet also comprises a tablet core boosting layer, and the prescription mainly comprises a filling agent, an adhesive and a lubricant, so that the tablet has the function of assisting in drug release. The formulation of the boosting layer can be selected from the same types as the medicament-containing layer of the tablet core, and for example, the filling agent is preferably one or more of sodium chloride, lactose, polyoxyethylene, mannitol, sorbitol and xylitol. In the formula of the tablet core boosting layer, the adhesive can be polyvinylpyrrolidone, hydroxypropyl methylcellulose and the like; the lubricant is selected from one or more of stearic acid, magnesium stearate and sodium stearate fumarate, preferably magnesium stearate or sodium stearate fumarate. In the boosting layer, the using amount of the adhesive is 3% -10% of the total amount of auxiliary materials of the boosting layer, and the optimal selecting amount is 4-6%; the dosage of the lubricant is 2 to 3 percent of the total amount of the auxiliary materials; the balance being filler.
In the invention, the controlled-release film layer is wrapped on the double-layer tablet core, and is a film coating which mainly controls the release speed of the medicine. The controlled release film layer is mainly formed by a film coating material and a pore-forming agent and is provided with a plurality of drug release holes. Wherein, the film coating material is preferably cellulose acetate. The control agent is also called release rate regulator, and can adopt one or more of hydroxypropyl cellulose and polyethylene glycol.
The weight of each tablet of the controlled-release tablet containing the policosanol in the embodiment of the invention is changed along with the change of the content of the policosanol, and is about 10-40 times of the content of the policosanol, wherein the medicine-containing layer accounts for 25-50% of the weight of the whole tablet, the boosting layer accounts for 40-60% of the weight of the whole tablet, and the coating layer accounts for 5-15% of the weight of the whole tablet.
Some embodiments of the present invention provide a method for preparing a controlled-release tablet containing policosanol as described above, comprising the steps of:
mixing policosanol, a surfactant, a carrier material, an adhesive and a solvent to obtain a medicine-containing solution; the drug-containing solution, the filler and the lubricant are granulated by a wet method to obtain drug-containing layer granules;
respectively providing boosting layer particles and coating material solution;
tabletting the medicine-containing layer particles and the boosting layer particles to obtain a double-layer tablet core;
and coating the double-layer tablet core by adopting the coating material solution, and then punching to obtain the controlled-release tablet containing policosanol.
The specific types and the dosage of the effective components of the medicine and each auxiliary material are as described in the prescription above. In the specific embodiment of the invention, the surfactant, the carrier and the adhesive in the prescribed amount can be taken and respectively added into a certain amount of solvent under the stirring state, the solvent is uniformly dispersed, and the temperature is slowly increased to the set temperature to obtain the carrier solution. According to the embodiment of the invention, the policosanol with the formula amount is weighed, preferably added into the carrier solution in a stirring state, and continuously stirred until the policosanol is dissolved, so as to obtain a medicine-containing solution. The policosanol raw material meeting the national quality standard is adopted in the embodiment of the invention, and the auxiliary material is a corresponding commercial product.
In the embodiment of the invention, the filling agent with the prescription amount is weighed and placed in a granulation container for mixing, and then the medicine-containing solution is added into the granulation container for granulation; drying the granulated granules to obtain dry granules, and adding a prescription amount of lubricant for mixing to obtain the medicine-containing layer granules.
And tabletting the medicine-containing layer particles and the boosting layer particles to form a double-layer tablet core, and finally coating and punching medicine releasing holes to prepare the policosanol double-layer controlled release tablet.
In other embodiments of the present invention, the preparation method of the controlled release tablet containing policosanol comprises the following steps:
mixing policosanol, a surfactant, a carrier material and a solvent to obtain a medicine-containing solution; heating the medicine-containing solution to raise the temperature, and volatilizing the solvent to obtain a solid dispersion; the solid dispersion, the adhesive, the filler and the lubricant are subjected to wet granulation to obtain medicine-containing layer granules;
the rest steps are consistent with the preparation process.
The preferred embodiment of the present invention performs the preparation of the drug-containing layer granules according to the second mode, and the preparation process is described in detail below. The method comprises the steps of weighing a surfactant and a carrier according to the prescription amount, respectively adding the surfactant and the carrier into a certain amount of solvent under the stirring state, uniformly dispersing, and slowly heating to a set temperature to obtain a carrier solution. Wherein, the solvent can be selected from one or more of small molecular alcohol and ketone, preferably one or more of ethanol, propylene glycol, isopropanol and acetone, and more preferably ethanol and/or acetone. And the dosage of the solvent is 3-15 times, preferably 3-10 times of the amount of the policosanol.
In addition, the policosanol in the formula amount is weighed in the embodiment of the invention, is preferably added into the carrier solution in a stirring state, and is continuously stirred until the policosanol is dissolved, so that a medicine-containing solution is obtained. The policosanol can be dissolved in hot organic solvents, such as ethanol, propylene glycol, isopropanol and acetone, preferably ethanol and acetone; the temperature of mixing or dissolving is 40 ℃ to 100 ℃, preferably in the range of 50 ℃ to 90 ℃, such as 50 ℃, 60 ℃, 70 ℃ and the like.
In the embodiment of the invention, the medicine-containing solution containing policosanol, the surfactant and the carrier material is continuously heated to raise the temperature, wherein the temperature rise range is 40-100 ℃, and the preferred range is 50-90 ℃; the policosanol can be uniformly dispersed in a mixture of other surfactants and carriers after being dissolved in a hot organic solvent, can form a solid dispersion after the organic solvent is volatilized, and is obtained by low-temperature crushing and 100-mesh sieving. The solid dispersion is typically a light yellow solid; wherein the particle size of the policosanol is not more than 5 μm, the preferable range is not more than 1 μm, the solubility of the policosanol can be effectively increased, and the control of the release rate of the controlled release tablet in the release process is facilitated.
After the solid dispersion is obtained, the solid dispersion and the prescribed amount of filler are mixed together in a wet granulator, then a binder solution (which can be dissolved in a solvent in advance) is added into the granulation equipment for granulation, the granulated granules are dried to obtain dry granules, and finally, the prescribed amount of lubricant is added for mixing to obtain medicine-containing layer granules for later use. The wet granulation process of the present invention is not particularly limited, and may be carried out in a conventional manner.
According to the tablet core boosting layer formula, the preparation of boosting layer particles is carried out in the embodiment of the invention; the method specifically comprises the following steps:
(1) weighing the adhesive in the prescription amount, respectively adding the adhesive into a certain amount of solvent under the stirring state, and uniformly stirring and dispersing to obtain an adhesive solution;
(2) the prescribed amount of filler is weighed and placed in a granulation vessel for mixing. Adding the binder solution in the step (1) into the granulation container for granulation;
(3) drying the granulated particles to obtain dry particles, adding a lubricant in a prescription amount, and mixing to obtain the boosting layer particles for later use. Wherein, the solvent used for preparing the boosting layer particles is selected from one or more of ethanol, propylene glycol, isopropanol and acetone, and ethanol or acetone is preferred.
In addition, the embodiment of the invention prepares a coating material solution (coating solution for short): adding a certain amount of film coating material and pore-forming agent into solvent, stirring and dispersing uniformly to obtain coating material solution for later use. The optional types of the film coating material and the pore-foaming agent are as described above; the solvent involved may be one or more of water, ethanol, propylene glycol, isopropanol and acetone.
Finally, the obtained granules containing the medicine layer are filled into a double-layer tablet press for first tabletting, and after the first tabletting is finished, the granules containing the boosting layer are filled into the double-layer tablet press for second tabletting to obtain a double-layer tablet core; coating the double-layer tablet core by adopting the coating material solution to obtain a coated tablet; and (3) perforating the coated tablet by adopting a laser perforation technology or a mechanical perforation technology to obtain the policosanol controlled release tablet. The invention has no special limitation on the setting of the process parameters such as tabletting, coating, punching and the like, and all the process operations are commonly used by the people in the field.
After obtaining the controlled release tablet containing the policosanol, the dissolution rate of the controlled release tablet is determined by the embodiment of the invention. The controlled-release tablet is a medicine with a slow-release curative effect and capable of regulating dyslipidemia, and can slowly release policosanol at a relatively constant speed, so that the controlled-release tablet can be taken once a day, the taking frequency is reduced, and the compliance is improved. In addition, the preparation process is simple and feasible, and is suitable for large-scale industrial application.
For further understanding of the present application, the solid dispersion containing policosanol, the controlled release tablet and the preparation method thereof provided by the present application are specifically described below with reference to examples. It should be understood, however, that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention, which is defined by the following examples.
Example 1
The prescription of the medicine-containing layer of the tablet core is as follows:
the preparation process of the medicine-containing layer particles comprises the following steps:
(1) weighing the soybean phospholipid and the polyethylene glycol 6000 with the prescription amount, respectively adding the soybean phospholipid and the polyethylene glycol 6000 into the acetone with the prescription amount under the stirring state, uniformly dispersing, and slowly heating to 50 ℃.
(2) Weighing policosanol according to the prescription amount, adding the policosanol into the solution in the step (1) under the stirring state, and continuously stirring until the policosanol is dissolved to obtain a medicine-containing solution.
(3) Heating the solution containing the medicine in the step (2) continuously, obtaining light yellow solid after acetone is volatilized, crushing the solid at low temperature, and sieving the solid with a 100-mesh sieve.
(4) Weighing polyvinylpyrrolidone in a prescription amount, adding the polyvinylpyrrolidone in ethanol in the prescription amount, and stirring and dissolving to obtain an adhesive solution.
(5) Weighing lactose and polyoxyethylene in the prescription amount, and putting the lactose and polyoxyethylene in the prescription amount and the solid sieved by the 100-mesh sieve in the step (3) into a wet granulator together, and mixing.
(6) Adding the binder solution in the step (4) into a wet granulator for granulation.
(7) Drying the granulated granules to obtain dry granules, adding magnesium stearate in a prescription amount, and mixing to obtain medicine-containing layer granules for later use.
The formula of the tablet core boosting layer is as follows:
the preparation process of the boosting layer particles comprises the following steps:
(1) weighing polyvinylpyrrolidone in a prescription amount, adding the polyvinylpyrrolidone into ethanol in the prescription amount under a stirring state, and uniformly stirring and dispersing to obtain the adhesive solution.
(2) Lactose and polyoxyethylene in the prescribed amount are weighed and placed in a wet granulator for mixing. Adding the binder solution in the step (1) into a granulator for granulation.
(3) And drying the granulated granules to obtain dry granules, adding magnesium stearate in a prescription amount, and mixing to obtain the boosting layer granules for later use.
Coating formula:
the preparation process of the coating liquid comprises the following steps:
weighing the cellulose acetate, the hydroxypropyl cellulose and the polyethylene glycol according to the prescription amount, respectively adding the mixture into the mixed solution of water and acetone under the stirring state, and uniformly stirring and dispersing to obtain a coating material solution for later use.
The preparation process of the policosanol controlled release tablet comprises the following steps:
(1) and filling the medicine-containing layer granules into a double-layer tablet press for first tabletting, and filling the boosting layer granules into the double-layer tablet press for second tabletting after the first tabletting is finished to obtain the double-layer tablet core.
(2) And (3) coating the double-layer tablet core in the step (1) by adopting a coating material solution to obtain a coated tablet. Perforating the coated tablets by adopting a laser perforating technology to obtain about 10000 policosanol controlled release tablets; the content of policosanol in each controlled release tablet is 60 mg.
Example 2
The prescription of the medicine-containing layer of the tablet core is as follows:
the preparation process of the medicine-containing layer particles comprises the following steps:
(1) weighing sucrose ester, polyethylene glycol and polyvinylpyrrolidone according to the prescription amount, respectively adding into ethanol according to the prescription amount under the stirring state, uniformly dispersing, and slowly heating to 70 ℃.
(2) Weighing policosanol according to the prescription amount, adding the policosanol into the solution in the step (1) under the stirring state, and continuously stirring until the policosanol is dissolved to obtain a medicine-containing solution.
(3) Weighing sodium chloride and polyoxyethylene according to the prescription amount, and placing the sodium chloride and the polyoxyethylene in a fluidized bed granulator for mixing. Adding the solution in the step (2) into a fluidized bed granulator for granulation.
(4) Drying the granulated granules to obtain dry granules, adding a lubricant in a prescription amount, and mixing to obtain medicine-containing layer granules for later use.
The formula of the tablet core boosting layer is as follows:
the preparation process of the boosting layer particles comprises the following steps:
(1) weighing hydroxypropyl cellulose with the formula amount, adding the hydroxypropyl cellulose into ethanol with the formula amount under the stirring state, and uniformly stirring and dispersing to obtain the adhesive solution.
(2) Weighing sodium chloride and polyoxyethylene according to the prescription amount, and placing the sodium chloride and the polyoxyethylene in a wet granulator for mixing. Adding the binder solution in the step (1) into a granulator for granulation.
(3) And drying the granulated particles to obtain dry particles, adding a lubricant in a prescription amount, and mixing to obtain the boosting layer particles for later use.
Coating formula:
the preparation process of the coating liquid comprises the following steps:
weighing the cellulose acetate, the hydroxypropyl cellulose and the polyethylene glycol according to the prescription amount, respectively adding the mixture into the mixed solution of water and acetone under the stirring state, and uniformly stirring and dispersing to obtain a coating material solution for later use.
The preparation process of the policosanol tablets comprises the following steps:
(1) and filling the medicine-containing layer granules into a double-layer tablet press for first tabletting, and filling the boosting layer granules into the double-layer tablet press for second tabletting after the first tabletting is finished to obtain the double-layer tablet core.
(2) And (3) coating the double-layer tablet core in the step (1) by adopting a coating material solution to obtain a coated tablet. And (3) perforating the coated tablets by adopting a laser perforating technology to obtain about 10000 policosanol controlled release tablets.
Example 3
The prescription of the medicine-containing layer of the tablet core is as follows:
the preparation process of the medicine-containing layer particles comprises the following steps:
(1) weighing polyoxyethylene oleate, polyethylene glycol and polyvinylpyrrolidone in the prescription amount, respectively adding the polyoxyethylene oleate, polyethylene glycol and polyvinylpyrrolidone in 70% ethanol in the prescription amount under the stirring state, uniformly dispersing, and slowly heating to 70 ℃.
(2) Weighing policosanol according to the prescription amount, adding the policosanol into the solution in the step (1) under the stirring state, and continuously stirring until the policosanol is dissolved to obtain a medicine-containing solution.
(3) Heating the solution containing the medicine in the step (2) continuously, obtaining light yellow solid after the ethanol is volatilized, crushing the solid at low temperature, and sieving the solid with a 100-mesh sieve.
(4) And (4) mixing the medicine-containing powder sieved by the 100-mesh sieve in the step (3) with the sodium chloride and the polyoxyethylene in the prescribed amount in a wet granulating machine.
(5) Weighing 30% of ethanol according to the prescription amount, and adding the ethanol into the wet granulator in the step (4) for granulation.
(6) Drying the granulated granules to obtain dry granules, adding sodium stearyl fumarate with a prescribed amount, and mixing to obtain medicinal layer granules for later use.
The formula of the tablet core boosting layer is as follows:
the preparation process of the boosting layer particles comprises the following steps:
(1) weighing polyvinylpyrrolidone in a prescription amount, adding the polyvinylpyrrolidone into ethanol in the prescription amount under a stirring state, and uniformly stirring and dispersing to obtain the adhesive solution.
(2) Weighing sodium chloride and polyoxyethylene according to the prescription amount, and placing the sodium chloride and the polyoxyethylene in a wet granulator for mixing. Adding the binder solution in the step (1) into a granulator for granulation.
(3) And drying the granulated particles to obtain dry particles, adding a lubricant in a prescription amount, and mixing to obtain the boosting layer particles for later use.
Coating formula:
the preparation process of the coating liquid comprises the following steps:
weighing the cellulose acetate, the hydroxypropyl cellulose and the polyethylene glycol according to the prescription amount, respectively adding the mixture into the mixed solution of water and acetone under the stirring state, and uniformly stirring and dispersing to obtain a coating material solution for later use.
The preparation process of the policosanol tablets comprises the following steps:
(1) and filling the medicine-containing layer granules into a double-layer tablet press for first tabletting, and filling the boosting layer granules into the double-layer tablet press for second tabletting after the first tabletting is finished to obtain the double-layer tablet core.
(2) And (3) coating the double-layer tablet core in the step (1) by adopting a coating material solution to obtain a coated tablet. And (3) perforating the coated tablets by adopting a laser perforating technology to obtain about 10000 policosanol controlled release tablets.
Comparative example 1
The prescription of the medicine-containing layer of the tablet core is as follows:
the preparation process of the medicine-containing layer particles comprises the following steps:
(1) weighing policosanol according to the prescription amount, adding the policosanol into ethanol according to the prescription amount under the stirring state, continuously stirring, and slowly heating to 50 ℃ to obtain a drug-containing suspension.
(2) Weighing hydroxypropyl cellulose, starch and polyoxyethylene according to the prescription amount, placing the hydroxypropyl cellulose, the starch and the polyoxyethylene into a wet granulator, and mixing.
(3) Adding the suspension containing the medicine in the step (1) into a wet granulating machine for granulating.
(4) Drying the granulated granules to obtain dry granules, adding magnesium stearate in a prescription amount, and mixing to obtain medicine-containing layer granules for later use.
The formula of the tablet core boosting layer is as follows:
the preparation process of the boosting layer particles comprises the following steps:
(1) weighing polyvinylpyrrolidone in a prescription amount, adding the polyvinylpyrrolidone into ethanol in the prescription amount under a stirring state, and uniformly stirring and dispersing to obtain the adhesive solution.
(2) The polyoxyethylene with the prescription amount is weighed and placed in a wet granulator. Adding the binder solution in the step (1) into a granulator for granulation.
(3) And drying the granulated granules to obtain dry granules, adding magnesium stearate in a prescription amount, and mixing to obtain the boosting layer granules for later use.
Coating formula:
the preparation process of the coating liquid comprises the following steps:
weighing the cellulose acetate, the hydroxypropyl cellulose and the polyethylene glycol according to the prescription amount, respectively adding the mixture into the mixed solution of water and acetone under the stirring state, and uniformly stirring and dispersing to obtain a coating material solution for later use.
The preparation process of the policosanol tablets comprises the following steps:
(1) and filling the medicine-containing layer granules into a double-layer tablet press for first tabletting, and filling the boosting layer granules into the double-layer tablet press for second tabletting after the first tabletting is finished to obtain the double-layer tablet core.
(2) And (3) coating the double-layer tablet core in the step (1) by adopting a coating material solution to obtain a coated tablet.
(3) And (3) perforating the coated tablets by adopting a laser perforating technology to obtain about 10000 policosanol controlled release tablets.
Dissolution determination
Putting 6 policosanol controlled release tablets prepared above into a dissolution cup, wherein the dissolution medium is phosphate buffer solution with pH6.8, the temperature is 37 ℃, and the stirring speed is 50 r/min. Sampling at 1h, 2h, 4h, 8h, 12h, 18h and 24h, determining the content of octacosanol by gas chromatography, calculating the release amount of the polycosanol controlled release tablet at different time points according to the content, and taking an average value.
Specific release data are shown in table 1:
TABLE 1 Release degree data of policosanol controlled release tablets in phosphate buffer of pH6.8
As can be seen from the table, in the formulation of comparative example 1, there were no surfactants, water-soluble fillers, etc., resulting in that the cumulative amount of policosanols released in the release medium at each time point was much smaller than that of 3 examples of the present invention, and the release was not complete at 24 hours, failing to achieve the desired effect of controlled release of the drug.
Compared with the traditional policosanol tablet, the invention can greatly reduce the particle size of the policosanol in the medicament, improve the dispersion degree and the solubility of the policosanol, control the release rate of the policosanol, prolong the release time and the administration interval, and further improve the bioavailability of the policosanol in a human body and the administration compliance of the policosanol.
The above description is only a preferred embodiment of the present invention, and it should be noted that various modifications to these embodiments can be implemented by those skilled in the art without departing from the technical principle of the present invention, and these modifications should be construed as the scope of the present invention.
Claims (11)
1. The solid dispersion containing the policosanol is characterized by comprising the policosanol, a surfactant and a carrier, wherein the surfactant is a nonionic surfactant for assisting dispersion; the particle size of the policosanol in the solid dispersion is not more than 5 mu m, and the preferable range is not more than 1 mu m.
2. The solid dispersion of claim 1, wherein the surfactant is selected from one or more of sucrose esters, phospholipids, polysorbates, and polyoxyethylene fatty acid esters; the carrier is selected from one or more of polyethylene glycol and polyvinylpyrrolidone.
3. A controlled-release tablet containing policosanol, which is characterized by comprising: a double-layer tablet core and a controlled release film layer wrapping the double-layer tablet core; the double-layer tablet core consists of a medicine-containing layer and a boosting layer;
the medicine-containing layer comprises policosanol, a surfactant, a filler, a carrier, an adhesive and a lubricant; the surfactant is a nonionic surfactant for assisting dispersion; the content of policosanol in each controlled release tablet is above 5mg, preferably 5mg-80mg, more preferably 10mg-60 mg.
4. The controlled-release tablet according to claim 3, wherein the surfactant is selected from one or more of sucrose esters, phospholipids, polysorbates, and polyoxyethylene fatty acid esters; the content of the surfactant is 0.5-10 times of the mass of the policosanol, the preferable range is 0.5-5 times, and the more preferable range is 0.5-3 times.
5. Controlled release tablet according to claim 4, characterized in that the filler is a water soluble filler, preferably one or more of sodium chloride, lactose, polyoxyethylene, mannitol, sorbitol and xylitol, more preferably a combination of at least two of polyoxyethylene, sodium chloride and lactose.
6. The controlled-release tablet according to any one of claims 3 to 5, wherein the carrier is selected from one or more of polyethylene glycol and polyvinylpyrrolidone; the content of the carrier is 1-20 times, preferably 2-10 times of the mass of the policosanol.
7. Controlled release tablet according to any of claims 3 to 5, wherein the lubricant is selected from one or more of stearic acid, magnesium stearate and sodium fumarate stearate, preferably sodium fumarate stearate; the adhesive is selected from one or more of polyvinylpyrrolidone, hypromellose and hydroxypropyl cellulose.
8. The controlled-release tablet according to any one of claims 3 to 5, wherein the controlled-release film layer is mainly formed of a film coating material and a pore-forming agent, and has a plurality of drug release pores.
9. The process for the preparation of the policosanol-containing controlled release tablet according to any of the claims from 3 to 8, comprising the following steps:
mixing policosanol, a surfactant, a carrier material and a solvent to obtain a medicine-containing solution; the drug-containing solution, the filler and the lubricant are granulated by a wet method to obtain drug-containing layer granules; optionally adding a binder to the drug-containing solution or during wet granulation;
respectively providing boosting layer particles and coating material solution;
tabletting the medicine-containing layer particles and the boosting layer particles to obtain a double-layer tablet core;
and coating the double-layer tablet core by adopting the coating material solution, and then punching to obtain the controlled-release tablet containing policosanol.
10. The preparation method according to claim 9, characterized in that the medicated solution containing policosanol, surfactant and carrier material is heated to raise the temperature, and the solvent is volatilized, so as to obtain a solid dispersion of policosanol with particle size not greater than 5 μm; the solid dispersion, the adhesive, the filler and the lubricant are subjected to wet granulation to obtain the drug-containing layer granules.
11. The method according to claim 9 or 10, wherein the solvent is selected from one or more of small-molecule alcohols and ketones, preferably one or more of ethanol, propylene glycol, isopropanol, and acetone; the mixing temperature is from 40 ℃ to 100 ℃, preferably in the range of from 50 ℃ to 90 ℃.
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